Heart as Electrical Organ

Ion Channels Research

Use with Pacemakers

Genesis of Virtual Heart

Physiome, the Company

Biotech Opportunity: Drugs, But No Needles

Corrections or additions?

Meet the Computer with the Working Heart

This article by Christopher Mario was published

in U.S. 1 Newspaper on May 13, 1998. All rights reserved.

When F. Scott Fitzgerald famously declared that there

are no second acts in American lives, he wasn’t counting on guys like

Bill Scott. After leaving his job as head of worldwide research for

Bristol Myers-Squibb in 1996, Scott, now 58, could have done a number

of things.

He could have returned to academe, having been a researcher at the

prestigious medical institution Rockefeller University for 16 years

before jumping to industry in 1983. He could have joined a bunch of

boards of directors. He could have become a consultant. Or he could

have landed on some tropical island somewhere under his golden

parachute

of heftily appreciated Bristol Myers stock options, there to live

out his days in splendid and well-earned repose.

Instead he signed on as CEO of a start-up biotech company with a

technology

so advanced it sounds like science fiction.

Scott’s company, Physiome Sciences, has a $2 million supercomputer

purring away at its College Road offices. Performing dozens of

complicated

equations simultaneously, the computer holds within its electronic

brain a fully functional, three-dimensional, interactive model of

a working heart. The result of 30 years of research and made possible

only recently by significant advances in computing power, Physiome’s

"virtual heart" is expanding the horizons of understanding

of the organ whose various malfunctions are together the leading cause

of death in the United States (http://www.physiome.com).

This heart is not just some high-tech computer game. And it’s not

just an animated picture of a beating organ, although it does offer

a graphical interface. Rather, Physiome’s virtual heart is an

incredibly

detailed math-based model of how the heart actually works. Not just

that it beats, but why and how it beats.

Based on what until just a few years ago had been the entirely

theoretical

work of an Oxford physiologist named Denis Noble, the virtual heart

provides a quantitative, comprehensive, verifiable, and usefully

predictive

model of the heart based on the properties of the heart’s individual

cells and the biochemical functions they perform. Translation: the

virtual heart breaks down the millions and millions of biological

processes going on inside the heart, describes them as mathematical

equations, and then assembles them and all their actions and

interactions

to create an electronic heart that "works" just like a real

one.

That alone would be impressive, a technological feat that even five

years ago was pure science-fiction, the medical equivalent of cold

fusion. But Physiome’s virtual heart does much more than merely mimic

the function of the heart. Because the known mechanics of the heart’s

most basic cellular functions underlie this virtual heart, it’s

possible

to reprogram the heart by changing the equations that describe those

cellular functions.

Which means that Physiome researchers can program their virtual heart

to have a heart attack, or develop congestive heart failure, or go

into arrhythmia. Stuff that happens to real hearts, inside real

people,

every day.

And that’s what makes Physiome interesting. If you can create a model

that demonstrates what goes wrong in a heart based on the actual

physiological

and biochemical processes responsible, you’re that much closer to

figuring out how to fix it.

Top Of Page
Heart as Electrical Organ

You have probably never given much thought to how and

why your heart works, but Bill Scott will tell you anyway:

electricity.

"The heart is an electrical organ," Scott explains. "What

drives the heart to contract and relax is the movement of calcium

and other ions in and out of cells. As a result of that ion movement,

you get voltage movements across the surface of the heart. That’s

what an electrocardiogram (ECG) measures. When you put electrodes

on a person’s chest, what you see is a complicated series of peaks

and valleys, which represent voltage moving across the heart."

Physiome’s virtual heart is built on mathematical descriptions of

the major gene products of the cells of the heart. Most of these gene

products regulate ion channels — routes across which calcium,

sodium, potassium, and other ions move in and out of cells, and in

so doing create the electrical charges that power the heart. You need

a supercomputer to do this — Physiome has a Silicon Graphics 32

parallel processor — because we’re talking about a lot of gene

products, a lot of ions, and literally millions of equations to

explain

them all — what computer types call "embarrassingly parallel

problems."

"These descriptions are based on experimental data, and are

validatable

in the sense that taken together, they behave correctly," Scott

says of the mathematical descriptions of the ion channels that make

the virtual heart work. These descriptions, all of which are based

on actual physical data collected in experiments on real hearts by

literally thousands of scientists over many years, even enable

Physiome’s

virtual heart to generate its own ECG.

Top Of Page
Ion Channels Research

Much is already known about these ion channels, which

have been a major area of cardiovascular research for some time. That

research has led to a discovery you have probably heard about if you

or someone you know has heart disease: the calcium channel blocker.

A class of drugs like Pfizer’s Procardia XL, calcium channel blockers

inhibit the transfer of calcium ions across cell membranes in the

heart and other muscles, causing the heart to relax and the arteries

to dilate, thereby reducing angina and high blood pressure.

Research on ion channels has also shown that in a failing heart, the

gene products that regulate the movement of ions in and out of cells

change in four major ways. Physiome used that data to reprogram its

virtual heart to behave like the heart of someone with congestive

heart failure, a common condition in which the heart gradually loses

its ability to pump enough blood to satisfy the body’s needs.

"We went into our model and introduced those changes, and sure

enough, the model then behaved like a failing heart," Scott

reports.

"In the normal heart, when it contracts you see smooth movement

of voltage across the heart. In the congestive heart, you see major

arrythmias, which appear as spiraling waves of voltage changes, rather

than smooth movements of voltage, on an ECG. Basically, a heart in

congestive heart failure gets twitchy, and though you probably think

heart attacks kill the most people, 50 percent in fact die from this

kind of electrical instability."

Physiome’s ability to change their virtual heart from healthy to

impaired

proves the model works, Scott says. If you know that four cellular

changes occur in congestive heart failure in a real heart, and then

you program your virtual heart to include these four changes, your

virtual heart should exhibit exactly the same symptoms as the real

heart. And that’s just how it worked.

Even the Food and Drug Administration (FDA), which regulates and

approves

all prescription drugs in the United States, is convinced. Data

produced

by Physiome’s virtual heart recently saved a new calcium channel

blocker

submitted for review to the FDA by Swiss drug giant Roche from being

rejected.

"Just as they were finishing clinical trials" — testing

in humans — "they ran into a problem," Scott says of

Posicor,

the new Roche drug. "A small percentage of patients on the drug

developed abnormal ECGs. In just three weeks we demonstrated that

the changes were benign, and presented our findings to the FDA

advisory

committee considering the drug. Our findings turned around the

meeting.

Most of the questions were about the ECGs, and we were able to remove

that as a block to approval."

Which points up the most exciting potential use of the virtual heart:

to identify new potential drugs, and then to test them.

Most drugs today are developed in a process called rational drug

design.

Rational drug design uses a wide variety of technologies to elucidate

chemical functions that cause disease, and then seeks to identify

within those chemical functions likely targets for drug intervention.

Once the target is identified, drug researchers then search for a

chemical compound that will either inhibit or encourage the particular

biochemical activity identified as the target. Because Physiome’s

virtual heart is based on the basic chemical functions of the heart’s

cells, Scott believes it will enable researchers to tap a heretofore

unreachable cornucopia of new drug targets for heart disease.

"Our model has the descriptions of all the biochemical and

biophysical

aspects of the gene products controlling heart function," Scott

says. "Which means we can inhibit or stimulate each of those gene

products to look for changes that will be efficacious in treating

specific diseases."

At the same time, the virtual heart also provides a novel way to test

the efficacy of new drugs — a way that’s faster, cheaper, and

less ethically troubling than traditional animal testing. Just program

in the chemical changes your drug causes, and let the computer tell

you what happens.

"We can look at drug effects. We can look at dose response,"

Scott says. "This technology dramatically increases the speed

with which researchers can do their experiments, and enables them

to learn new things that they could not learn on an actual heart.

And it cuts down on the need to use experimental animals, which is

not only a cost issue but an ethical and emotional issue as well."

Top Of Page
Use with Pacemakers

A third major benefit of the virtual heart is in the area of

implantable

defibrillators, better known as pacemakers.

"People with defibrillators have a pretty horrible life,"

Scott says. "These are very sophisticated devices that have to

sense when the heart is beating abnormally, and then shock it back

into a normal rhythm. The problem is, they often go off spontaneously

and put the person into arrhythmia. So people live in fear of their

pacemakers going off. A lot end up in therapy."

Scott believes his virtual heart will eventually enable technicians

to pinpoint exactly where a pacemaker should be installed, and exactly

what it should do. Scott calls the virtual heart a "rational

design

tool" for implantable defibrillators that will enable the optimal

placement of electrodes and the development of just the right timing

and type of shocks — the "optimal shockwave form protocol"

— thus making pacemakers less likely to malfunction.

Top Of Page
Genesis of Virtual Heart

The advent of relatively cheap supercomputing power

has made Physiome’s virtual heart — and ideas like using it to

improve the lives of people with pacemakers — possible. But the

real genesis of the virtual heart occurred nearly 30 years ago in

England, long before supercomputers were even imaginable.

That was when Denis Noble began his career as a physiologist, and

devoted himself to figuring out exactly how the heart generates its

electrical charges. A pioneer in the field of integrative physiology

— taking all the disparate bits of data about cells’ functions

and integrating them into a model of how a cell or tissue or organ

works — Noble had been building single-cell models of cardiac

tissues for nearly three decades when he and another Oxford Ph.D.

named Jeremy Levin decided to explore how advances in computer

technology

might further Noble’s work.

Levin, who has run a number of biotech companies in his career,

brought

together Noble and a Johns Hopkins biomedical engineering and computer

science professor named Raimond Winslow. Noble and Winslow joined

forces, and with the later addition of a team of bioengineers from

New Zealand, created the first 3-D model of a human heart based on

Noble’s pioneering research into the functions of cardiac cells.

That was in 1993. By 1996, Levin and the scientists were ready to

form a company to commercialize their invention. They raised a $2.5

million in seed funding, and a year later, they hired Bill Scott.

Scott, the oldest child of six, grew up in Illinois, where his father

ran a hardware store. He majored in chemistry at the University of

Illinois, Class of 1962, and has a PhD in biochemistry from CalTech

with postdoc studies at Rockefeller University, where he taught for

16 years. He and his wife Lonna, a freelance medical illustrator,

have a grown daughter who is an attorney.

When he was the head of research for Bristol-Myers Squibb, he had

served on the board of a company called Cadus; its CEO was Jeremy

Levin. When Levin asked Scott to join in his new venture, Scott needed

little convincing.

"I got to know Jeremy well at Cadus," a publicly-traded

company

that has a yeast-based drug receptor identification technology useful

in rational drug design, "and it was clear to me that he had a

very unique technology. The most unique thing I’d seen anywhere."

Scott also saw in Physiome Sciences an opportunity to make a

difference.

"I wanted to go back and do something hands-on, rather than just

be a high-level bureaucrat, which was basically my job at B-MS,"

Scott says.

Since Scott joined, the company has raised $10 million to fund its

operations, chiefly from Oxford Bioscience Partners in Westport,

Connecticut,

but also from SR1, the investment arm of Smith Kline Beecham, based

in Radnor, Pennsylvania. This is enough to last two and a half years

without additional funding (which, like all start-ups, it continues

to seek).

The company has a functioning single-cell model that can run on

Windows

NT, it has the heart model, and is beginning work on a virtual kidney.

Top Of Page
Physiome, the Company

Physiome has 10 employees in Princeton; Scott expects to have about

25 by year’s end, and spends much of his time these days interviewing

candidates. Like most employers these days, he’s having a hard time

finding good software engineers, but the people who understand the

theory — the computational biologists — are contacting him,

Scott says.

"It’s the first commercial application in their area," Scott

says.

Running his small start-up is fun, Scott says. Without a huge

infrastructure,

it’s easy to get things done. But no infrastructure also has its

downside.

Last year the company was dealt a big blow by the state of New Jersey

when the state reneged on space it had promised to Physiome at the

New Jersey Technology Center in North Brunswick. Originally slated

as a high-tech incubator, the Center was instead leased to Merck (U.S.

1, February 25, 1998).

"That set us back two or three months," Scott reports. "We

had a signed deal, and there were a lot of incentives to go there,

like money for build-out, and suddenly it was gone. They called and

said, sorry."

The space problem solved with more expensive digs in 8,000 square

feet at 307 College Road East, Scott and his team are now focused

on seeking partnerships with drug and device research companies.

Physiome

will not lease or sell its software, but rather will enter into

collaborative

agreements with research teams at client companies, playing a role

in their work using Physiome’s virtual organs and single-cell models.

As for an IPO, Scott says that’s very premature. "We’re currently

very focused on three areas," Scott says. "One is hiring

scientists.

Two is working on developing our corporate partnerships. And three

is spending a lot of time out presenting the company. A major issue

for any small company is becoming known, and luckily for us that’s

very easy, because what we’re doing is so novel."

Physiome has gotten a ton of press in the past year: in addition to

the many medical and technology conferences at which he speaks, Scott

has also appeared on the BBC, German television, and CNN Financial.

Whether scientists or laypeople, everybody is amazed by the computer

with a working heart.

Physiome Sciences, 307 College Road East, Princeton

08540. Bill Scott, CEO. 609-987-1199; fax, 609-987-9393.

Top Of Page
Biotech Opportunity: Drugs, But No Needles

The intravenous solution you receive in a hospital

probably

didn’t start out as a liquid. A nurse took the powdered form of the

drug and liquefied it, using a needle to inject it into the IV bag.

If that sounds like a situation liable to infection, you’re right.

Raymond J. Scheire has a product that improves the safety and

convenience

of this crucial process. His Bio-Set line of drug delivery systems

enables pharmaceutical companies to differentiate their products to

more effectively compete with generics.

Scheire has opened a sales office at 5 Independence Way for Biodome,

which is based in Issoire, France. The firm’s CEO is Jacques Gardette,

and Scheire is the sales and marketing director of Biodome America

Inc.

"Our product is a device to reconstitute a powdered or lyophilized

(freeze-dried) drug," says Scheire. "It eliminates a

half-dozen

different components, it comes in one piece, and it comes with the

drug. Before you inject a drug you can reconstitute it without using

needles." Other advantages are prevention of needle stick injuries

and reduced potential for contamination.

Scheire believes his needleless Bio-Set products are more competitive

than those made in the United States. One of the products replaces

vial and syringe systems, and other reconstitutes powdered drugs into

infusion bags.

Bio-Set costs from 50 cents to $1.50 per unit, depending on volume,

and it is targeted to expensive drugs — such as oncology drugs,

certain vaccines, and drugs for multiple sclerosis, cardiovascular

disease, and hemophilia — which can cost from $100 to $500 per

dose.

"Our clients are looking to add value with a delivery system that

these drugs deserve," says Scheire. "With a needle and a

syringe

it is difficult to get a precise dosage. With two or three milligrams

worth $500 you don’t want to waste anything. It is awkward even for

an experienced nurse, but with our system you can be precise."

"Our device acts as a closure system to crimp the stopper on the

glass vial to have a hermetic, sterile system," he says. "The

key advantage of our system is that it can fit a traditional vial

and rubber stopper, so all we are replacing is the crimp. You need

a capping machine to push the Bio-Set on the vial. All our stability

studies are to prove it has the same closure integrity as the aluminum

crimp."

The increasing number of hospital infections helped to drive the move

toward needleless systems. In 1992 the American Society of Health

Care Pharmacies issued a mandate to use needleless systems as much

as possible, and hospital pharmacies started demanding them. "We

are not pushing a product, we are meeting market demand," says

Scheire. "If a drug company offers a delivery system and is

willing

to absorb the cost, it can go to hospital pharmacies and say, `We

are offering a delivery system that will make it easy to reconstitute

the drug,’ and that will increase market share, which offsets the

cost of the machine."

The products are being launched in 26 countries, and in the first

quarter of next year one is scheduled to be used by a New Jersey-based

pharmaceutical firm (unnamed, as yet) for the reconstitution of an

anti-infective drug administered with an IV bag.

Biodome has 70 percent of the hemodialysis market in France, and it

is distributing the products of a Japanese firm, including dialyzers,

hemostatic bandages, disposable blood line sets, catheters,

arterial/venous

fistula sets, and single patient dialysis units. It also distributes

polio vaccine systems in Europe under contract with the World Health

Organization.

Its clients include Hoechst Marion Roussel, Merck Sharp & Dohme,

Pasteur

Merieux, and Rhone Poulenc Rorer, Smith Kline Beecham, and

Bristol-Myers

Squibb, and Wyeth Ayerst, among others.

Born in Belgium, the 40-year-old Scheire migrated to Sydney,

Australia,

and then followed his future wife to the United States after she began

working in New York. He earned his BA and MBA in Sydney, has a

master’s

degree in food science from Rutgers’ Cook College, and worked for

a small company in the packaging industry before joining Biodome last

year, "To function in my position, it helps to have had a varied

background," says Scheire.

Biodome America, 5 Independence Way, Suite 300,

Princeton 08540. Raymond J. Scheire, sales and marketing director.

609-514-5170; fax, 609-514-5171. Home page:

http://www.biodome.firm.


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